Several naturally-occurring alkaloids obtainable from Vinca rosea have been found active in the treatment of experimental maliganancies in animals. Among these are leurosine (U.S. Pat. No. 3,370,057), vincaleukoblastine (vinblastine) to be referred to hereinafter as VLB (U.S. Pat. No. 3,097,137), leurosidine (vinrosidine) and leurocristine (VCR or vincristine) both in U.S. Pat. No. 3,205,220), deoxy VLB "A" and "B", Tetrahedron Letters, 783 (1968) (desacetyl leurosine hydrazide is also disclosed therein); 4-desacetoxyvinblastine (U.S. Pat. No. 3,954,773); 4-desacetoxy-3'-hydroxyvinblastine (U.S. Pat. No. 3,944,554); leurocolombine (U.S. Pat. No. 3,890,325), leuroformine (N-formylleurosine, see Belgian Pat. No. 811,110) and vincadioline (U.S. Pat. No. 3,887,565). Two of these alkaloids, VLB and leurocristine, are now marketed as drugs for the treatment of malignancies in humans, particularly the leukemias and related diseases.
The dimeric indoledihydroindole alkaloids obtainable from Vinca rosea can be represented by the formula: ##STR1##
In the above formula where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, VLB is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hyroxyl and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 and R.sup.5 are H and R.sup.4 is ethyl, deoxy VLB "A" is represented; where R.sup.1, R.sup.2 and R.sup.5 are the same as in deoxy VLB "A" but R.sup.3 is ethyl and R.sup.4 is hydrogen, deoxy VLB "B" is represented; and where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together form an .alpha.-epoxide ring, leurosine is represented.
Of the above alkaloids, vincristine is the most useful, and the least available, from Vinca. Recently, Jovanovics et al., U.S. Pat. No. 3,899,493, have developed a method for converting the relatively more abundant alkaloid VLB into vincristine in 50% or better yields by chromic acid oxidation at low (-60.degree. C.) temperatures.
Derivatives of vincristine substituted at C-5' are not recorded in the literature.